This invention relates to the use of compounds which are selective inhibitors of cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cGMP PDEs) in the treatment of erectile dysfunction (impotence) in male animals, including man.
Impotence can be defined literally as a lack of power, in the male, to copulate and may involve an inability to achieve penile erection or ejaculation, or both. More specifically, erectile impotence or dysfunction may be defined as an inability to obtain or sustain an erection adequate for intercourse. Its prevalence is claimed to be between 2 and 7% of the human male population, increasing with age, up to 50 years, and between 18 and 75% between 55 and 80 years of age. In the USA alone, for example, it has been estimated that there are up to 10 million impotent males, with the majority suffering from problems of organic rather than of psychogenic origin.
Reports of well-controlled clinical trials in man are few and the efficacy of orally administered drugs is low. Although many different drugs have been shown to induce penile erection, they are only effective after direct injection into the penis, e.g. intraurethrally or intracavernosally (i.c.), and are not approved for erectile dysfunction. Current medical treatment is based on the i.c. injection of vasoactive substances and good results have been claimed with phenoxybenzamine, phentolamine, papaverine and prostaglandin E1, either alone or in combination; however, pain, priapism and fibrosis of the penis are associated with the i.c. administration of some of these agents. Potassium channel openers (KCO) and vasoactive intestinal polypeptide (VIP) have also been shown to be active i.c., but cost and stability issues could limit development of the latter. An alternative to the i.c. route is the use of glyceryl trinitrate (GTN) patches applied to the penis, which has been shown to be effective but produces side-effects in both patient and partner.
As a general alternative to pharmacological intervention, a variety of penile prostheses has been used to assist achievement of an erection. The short term success rate is good, but problems with infection and ischaemia, especially in diabetic men, make this type of treatment a final option rather than first-line therapy.
According to the specification of our International patent application no PCT/EP94/01580, (publication no WO94/28902), we describe and claim the use of a series of pyrazolo [4,3-d]pyrimidin-7-ones for the treatment of impotence. The compounds are potent and selective inhibitors of cGMP PDE in contrast to their inhibition of cyclic adenosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cAMP PDEs). This selective enzyme inhibition leads to elevated cGMP levels which, in turn, provides the basis for the utilities previously disclosed for the compounds in the treatment of stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular disease, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome. The specification goes on to describe investigations which identified three PDE isoenzymes in human corpus cavenosum tissue, relaxation of which leads to penile erection. The predominant enzyme was found to be the cGMP-specific PDEV, while cGMP-stimulated cAMP PDEII and cGMP-inhibited cAMP PDEIII, were also present. The compounds described were found to be potent and selective inhibitors of the PDEV enzyme but demonstrated only weak inhibitory activity against the PDEII and PDEIII enzymes. This activity is believed to be responsible for the action of the compounds in the treatment of erectile dysfunction.
A number of cGMP-PDE inhibitors have previously been described in the literature for a variety of utilities, these include use in treating obstructive lung diseases such as asthma and brochitis, in combatting allergic diseases such as allergic asthma, allergic rhinitis, urticaria, and irritable bowel syndrome; and in combatting angina, hypertension and congestive heart failure. Utility has also been claimed as diuretics, as antiinflammatory agents, in the treatment of baldness, for conditions of reduced blood vessel patency, and in glaucoma. However there has not previously been any suggestion that any of these compounds would be of utility in the treatment of erectile dysfunction.
Thus the present invention provides the use of a compound which is a selective cGMP PDE inhibitor for the manufacture of a medicament for the treatment of erectile dysfunction in a male animal, including man, wherein said compound is:
i a 5-substituted pyrazolo [4,3-d]pyrimidine-7-one as disclosed in European patent application 0201188;
ii a griseolic acid derivative as disclosed in European patent applications No. 0214708 and 0319050;
iii a 2-phenylpurinone derivative as disclosed in European patent application 0293063;
iv a phenylpyridone derivative as disclosed in European patent application 0347027;
v a fused pyrimidine derivative as disclosed in European patent application 0347146;
vi a condensed pyrimidine derivative as disclosed in European patent application 0349239;
vii a pyrimidopyrimidine derivative as disclosed in European patent application 0351058;
viii a purine compound as disclosed in European patent application 0352960;
ix a quinazolinone derivative as disclosed in European patent application 0371731;
x a phenylpyrimidone derivative as disclosed in European patent application 0395328;
xi an imidazoquinoxalinone derivative or its aza analogue as disclosed in European patent application 0400583;
xii a phenylpyrimidone derivative as disclosed in European patent application 0400799;
xiii a phenylpyridone derivative as disclosed in European patent application 0428268;
xiv a pyrimidopyrimidine derivative as disclosed in European patent 0442204;
xv a 4-aminoquinazoline derivative as disclosed in European patent application 0579496;
xvi a 4,5-dihydro-4-oxo-pyrrolo[1,2-a]quinoxaline derivative or its aza analogue as disclosed in European patent application 0584487;
xvii a polycyclic guanine derivative as disclosed in International patent application WO91/19717;
xviii a nitrogenous heterocyclic compound as disclosed in International patent application WO93/07124;
xix a 2-benzyl-polycyclic guanine derivative as disclosed in International patent application WO 94/19351;
xx a quinazoline derivative as disclosed in U.S. Pat. No. 4,060,615;
xxi a 6-heterocyclyl pyrazolo [3,4-d]pyrimidin-4-one as disclosed in U.S. Pat. No. 5,294,612;
xxii a benzimidazole as disclosed in Japanese patent application 5-222000; or
xxiii a cycloheptimidazole as disclosed in European Journal of Pharmacology, 251, (1994), 1.
xxiv a N-containing heterocycle as disclosed in International patent application WO94/22855.